Epilepsy is a general term describing a group of central nervous system disorders that are characterized by recurrent seizures that are the outward manifestation of excessive and/or hyper-synchronous abnormal electrical activity of neurons of the cerebral cortex and other regions of the brain. This abnormal electrical activity can be manifested as motor, convulsion, sensory, autonomic, or psychic symptoms.
Epilepsy affects millions of people worldwide, and over 2.5 million individuals in the United States. For the purposes of clinical assessment, it is useful to classify patients according to the type of seizure the patient experiences. As described in The Pharmacological Basis of Therapeutics, 9th Ed. (McGraw-Hill) [1], there are two classes of seizures: partial seizures and generalized seizures. Partial seizures consist of focal and local seizures. Partial seizures are further classified as simple partial seizures, complex partial seizures and partial seizures secondarily generalized. Generalized seizures are classified as convulsive and nonconvulsive seizures. They are further classified as absence (previously referred to as ‘petit mal’) seizures, atypical absence seizures, myoclonic seizures, clonic seizures, tonic seizures, tonic-clonic seizures, and atonic seizures.
Hundreds of epileptic syndromes have been defined as disorders characterized by specific symptoms that include epileptic seizures. These include, but are not limited to, absence epilepsy, psychomotor epilepsy, temporal lobe epilepsy, frontal lobe epilepsy, occipital lobe epilepsy, parietal lobe epilepsy, Lennox-Gastaut syndrome, Rasmussen's encephalitis, childhood absence epilepsy, Ramsay Hunt Syndrome type II, benign epilepsy syndrome, benign infantile encephalopathy, benign neonatal convulsions, early myoclonic encephalopathy, progressive epilepsy and infantile epilepsy. A patient may suffer from any combination of different types of seizures. Partial seizures are the most common, and account for approximately 60% of all seizure types. Regardless of the type of epilepsy, seizures significantly limit the autonomy of the patient.
It is believed that the characteristic seizures of epilepsy are caused by the disordered, synchronous, and rhythmic firing of brain neurons. The neurons can fire at up to four times their normal rate. As a result, epileptic seizures are an overstimulation of the normal neuronal processes that control brain function.
Anti-epileptic drugs are available for treating epilepsies, but these agents have a number of shortcomings. For instance, the agents are often poorly soluble in aqueous and biological fluids or are extremely hygroscopic. Of even greater importance is that patients often become refractory to a drug over time. In addition, many anti-epileptic agents cause unwanted side effects, neurotoxicities, and drug interactions. Even while being treated with one or a combination of the anti-epileptic drugs currently in clinical use, 30% of epileptic patients still experience seizures. As more anti-epileptic drugs are developed, the clinician will have expanded pharmaceutical options when designing an effective treatment protocol for each patient. Accordingly, a continuing need exists for pharmaceutical compositions that treat or prevent epilepsy and its associated symptoms with minimal side effects.
After experimentation and investigation, it has been discovered that oral and intraperitoneal administration of a therapeutic compound comprising formula (I) below to mice and rats resulted in profound and reproducible anticonvulsant or antiepileptic activity in animal modes of seizure disorders. It has further been discovered that these compounds do not show acute neurotoxic effects at the levels required for a therapeutic response.